Intermediates for (1,5) 6,6-Dimethyl-4-Hydroxy-3-oxabicyclo (3,1,0) Hexan-2-one and its ethers

ABSTRACT

A process for the preparation of compounds of the (1RS, 4RS, 5SR), (1R, 4R, 5S) or (1S, 4S, 5R) configuration having the formula ##STR1## wherein Y is selected from the group consisting of hydrogen and the organic residue Z of an optionally chiral alcohol of the formula ZOH comprising reacting in the presence of an acid agent 5RS-hydroxy-2,5-dihydrofuran-2-one having the formula ##STR2## either (a) with an achiral alcohol of the formula ZOH to obtain the resulting ether and reacting the latter in an anhydrous medium with an isopropylidene sulfurane of the formula ##STR3## wherein R 1  and R 2  are individually selected from the group consisting of optionally substituted monocyclic aromatic groups, isopropyl, groups and tertiary alkyl groups, to obtain a compound of formula I of the (1RS, 4RS, 5SR) configuration and Y is Z and optionally hydrolyzing the latter in acid medium to obtain the compound of formula I wherein Y is hydrogen or (b) with an optically active chiral alcohol of the formula ZOH to obtain a mixture of stereoisomeric ether due to the asymetrical carbon in the 5-position which mixture is rich in one of the two diastereoisomers, separating the diastereoisomeric ethers by physical means and reacting the separated diastereoisomers with the compound of formula II in anhydrous medium to obtain the compound of formula I with (1R, 4R, 5S) or (1S, 4S, 5R) configuration wherein Y is Z and optionally hydrolyzing the latter in an acid media to obtain the compound of formula I wherein Y is hydrogen and novel intermediates. The compounds of formula I where Y is hydrogen are described in French Pat. No. 1,580,474 and are interemediates for diversely substituted cyclopropane carboxylic acids whose esters are may active insecticides.

PRIOR APPLICATION

This application is a divisional of copending U.S. patent applicationSer. No. 759,477, filed July 25, 1985, now abandoned, which is adivisional application of copending application Ser. No. 582,321, filedFeb. 22, 1984, now abandoned, which in turn is a continuation ofcopending application Ser. No. 361,780, filed Mar. 25, 1982, nowabandoned, which in turn is a continuation of application Ser. No.170,093, filed July 18, 1980, now abandoned.

OBJECTS OF THE INVENTION

It is an object of the invention to provide an improved process for thepreparation of the various stereoisomers of (1,5)6,6-dimethyl-4-hydroxy-3-oxabicyclo (3,1,0) hexan-2-ones of formula I.

It is another object of the invention to provide novel intermediatecompounds.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel process of the invention for the preparation of compounds ofthe (1RS, 4RS, 5SR), (1R, 4R, 5S) or (1S, 4S, 5R) configuration havingthe formula ##STR4## wherein Y is selected from the group consisting ofhydrogen and the organic residue Z of an optionally chiral alcohol ofthe formula ZOH comprises reacting in the presence of an acid agent5RS-hydroxy-2,5-dihydrofuran-2-one having the formula ##STR5## either(a) with an achiral alcohol of the formula ZOH to obtain the resultingether and reacting the latter in an anhydrous medium with anisopropylidene sulfurane of the formula ##STR6## wherein R₁ and R₂ areindividually selected from the group consisting of optionallysubstituted monocyclic aromatic groups, isopropyl groups and tertiaryalkyl groups, to obtain a compound of formula I of the (1RS, 4RS, 5SR)configuration and Y is Z and optionally hydrolyzing the latter in acidmedium to obtain the compound of formula I wherein Y is hydrogen or (b)with an optically active chiral alcohol of the formula ZOH to obtain amixture of stereoisomeric ethers due to the asymetrical carbon in the5-position which mixture is rich in one of the two diastereoisomers,separating the diastereoisomeric ethers by physical means and reactingthe separated diastereoisomers with the compound of formula III inanhydrous medium to obtain the compound of formula I with (1R,4R,5S) or(1S,4S,5R) configuration wherein Y is Z and optionally hydrolyzing thelatter in an acid media to obtain the compound of formula wherein Y ishydrogen.

Examples of R₁ and R₂ are phenyl and phenyl optionally substituted withmethyls.

The preferred sulfurane of formula III is diphenyl isopropylidenesulfurane and the sulfuranes of formula III may be prepared by reactinga base with a salt of the corresponding isopropyl sulfonium, preferablya fluoroborate salt.

The acid agent present in the reaction of the alcohol ZOH and thecompound of formula II is preferably selected from the group consistingof sulfonic acids, sulfuric acid, hydrochloric acid and phosphoric acid,most preferably p-toluene sulfonic acid. The reaction with the sulfuraneof formula III is preferably effected in a solvent selected from thegroup consisting of dimethyl ether or diethyl ether of diethyleneglycol,ether, dimethylsulfoxide, tetrahydrofuran or dimethoxyethane andespecially in tetrahydrofuran and the formation of the cyclopropyl ringis effected at -90° to -30° C.

The optional hydrolysis of the ethers of formula I is preferablyeffected with a strong acid in the presence of water and awater-miscible solvent capable of dissolving the compound to behydrolyzed. The strong acid is preferably selected from the groupconsisting of sulfonic acids, sulfuric acid, hydrochloric acid andphosphoric acid and the solvent is preferably selected from the groupconsisting of alkanols, dioxane, tetrahydrofuran, dimethylformamide andcertain aliphatic ketones.

In a preferred embodiment of the invention, the alcohol ZOH is methanoland the 5(RS)-methoxy-2,5-dihydrofuran-2-one is reacted with diphenylisopropylidene sulfurane to obtain (1RS, 5SR)6,6-dimethyl-4(RS)-methoxy-3-oxabicyclo (3,1,0) hexan-2-one which isthen subjected to acid hydrolysis to obtain (1RS, 5SR)6,6-dimethyl-4(RS)-hydroxy-3-oxabicyclo (3,1,0) hexan-2-one.

In another preferred embodiment of the invention,S-(α-methyl-3-phenoxyphenyl)-methanol is reacted with5RS-hydroxy-2,5-dihydrofuran-2-one to obtain a mixture of5R-[1S-(3-phenoxyphenyl)-α-methylmethoxy]-2,5-dihydrofuran-2-one and5S-[1S-(3-phenoxyphenyl)-α-methylmethoxy]-2,5-dihydrofuran-2-one richerin the 5R isomer than the 5S isomer, separating the mixture bychromatography, reacting the 5R isomer with diphenylisopropylidenesulfurane to obtain (1R, 5S)6,6-dimethyl-4R-[1S-(3-phenoxyphenyl)-α-methylmethoxy]-3-oxabicyclo(3,1,0) hexan-2-one and optionally subjecting the latter to acidhydrolysis to form (1R, 5S), 6,6-dimethyl-4R-hydroxy-3-oxabicyclo(3,1,0) hexan-2-one.

In a modification of the latter process, after the chromatographicseparation, the 5S isomer is reacted with diphenylisopropylidenesulfurane to obtain (1S,5R)6,6-dimethyl-4S-[1S-(3-phenoxyphenyl)-α-methylmethoxy]-3-oxabicyclo(3,1,0) hexan-2-one and optionally subjecting the latter to acidhydrolysis to obtain (1S, 5R) 6,6-dimethyl-4S-hydroxy-3-oxabicyclo(3,1,0) hexan-2-one.

In a further embodiment of the process of the invention, l-menthol isreacted with 5RS-hydroxy-2,5-dihydrofuran-2-one to obtain a mixture of5R-[1R, 2S, 5R] 2-prop-2-yl-5-methylcyclohexyloxy-2,5-dihydrofuran-2-oneand 5S [1R,2S,5R]-2-prop-2-yl-5-methyl-cyclohexyloxy-2,5-dihydrofuran-2-one richerin the 5R isomer than the 5S isomer, separating the isomers bycrystallization, reacting the 5R isomer with diphenylisopropylidenesulfurane to obtain (1R, 4R, 5S)6,6-dimethyl-4-[(1R,2S,5R)-2-prop-2-yl-5-methyl-cyclohexyloxy]-3-oxabicyclo(3,1,0) hexan-2-one and optionally subjecting the latter to acidhydrolysis to obtain (1R, 5S) 6,6-dimethyl-4R-hydroxy-3-oxabicyclo(3,1,0) hexan-2-one.

In a modification of the latter embodiment of the process of theinvention, after separation by crystallization, the 5S isomer isisolated by chromatography and reacted with diphenylisopropylidenesulfurane to obtain (1S, 4S, 5R) 6,6-dimethyl-4-[1R, 2S,5R)-2-propy-2-yl-5-methyl-cyclohexyloxy]-3-oxabicyclo (3,1,0)hexan-2-one and optionally subjecting the latter to acid hydrolysis toobtain (1S, 5R) 6,6-dimethyl-4S-hydroxy-3-oxabicyclo (3,1,0)hexan-2-one.

In the process of the invention, analytical methods such aschromatography in high performance liquid phase (H.P.L.C.) permit one toknow that the reaction of an optically active chiral alcohol with5RS-hydroxy-2,5-dihydrofuran-2-one results in an asymetric inductionwhereby the raw reaction product is richer in one of the twodiastereoisomers than the other. For example, in the case of the ethersof S α-methyl-3-phenoxyphenyl methanol, the ratio of ##EQU1## instead ofthe theoretical 50% and in the case of ethers of l-menthol, the saidratio equals 59%. The existence of these 2 cases of asymetric inductionshows that the choice of a chiral alcohol permits the obtention of amixture richer in the desired stereochemical form and aids to isolateonly this form.

It is noted that in the case of the ether of l-menthol, after separationof 5R [1R, 2S, 5R]2-prop-2-yl-5-methylcyclohexyloxy-2,5-dihydrofuran-2-one, the resultingmother liquors after heating in an acid media lead to a new mixture ofthe R isomer and the S isomer in a proportion which is close to that ofthe initial mixture. One can repeat the procedure and thus isolate againthe R isomer and obtain in several successive operations, a high yieldof the R isomer.

This phenomenon is general for physical methods such as crystallizationor chromatography to separate the two stereoisomer forms after which themother liquors are heated in an acid media to obtain a new initialequilibrium of the R and S forms which can again be separated.Repetition of this procedure permits one to obtain a higher yields ofone of the stereoisomer forms.

The stereoselectivity of the reaction of the sulfurane with thecompounds of formula II is a particular advantage which permits theobtention of the compounds of formula I in only the desired stereoisomerform without any side reactions. Without limiting the scope of theinvention, it is believed that the stereoselectivity of the reaction isdue to the primary attack of the sulfurane on the 4-carbon atom of thefuranone which uniquely is in the trans form with respect to the 5-OZgroup. The final cyclization leads to a bicyclohexyl (3,1,0) derivativeof the cis structure with the group OZ being exo. Finally, since thecompounds of formula I contain 3 asymetric centers, the process of theinvention results in a racemate when the alcohol Z-OH used is achiral orone of two corresponding enantiomorphs when the alcohol ZOH is chiraland which can be separated from the starting two diastereoisomericethers of 5-hydroxy-2,5-dihydrofuran-2-one.

The process of the invention has great advantages in that the startingmaterials are simple and inexpensive and in requiring only two reactionsteps to permit access to the desired stereoisomeric forms of ethers of(1,5) 6,6-dimethyl-4-hydroxy-3-oxabicyclo (3,1,0) hexan-2-one and byhydrolysis, the stereoisomer forms of the corresponding 4-hydroxyderivatives.

Among the novel products of the invention are all the stereoisomericforms, in the pure state or in the form of mixtures of the ethersobtained by the reaction of the compound of formula II and ZOH wherein Zis other than methyl or ethyl as well as the compounds of formula Iwherein Y is other than methyl or ethyl.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE 1 (1RS, 5SR) 6,6-dimethyl-4-(RS)-methoxy-3-oxabicyclo [3,1,0]hexan-2-one

2 ml of a solution of 1.6M of tert.-butyllithium in pentane was addeddropwise at -70° C. under an inert atmosphere to a stirred mixture of950 mg of the tetrafluoroborate of isopropyldiphenylsulfonium in 15 mlof tetrahydrofuran and the mixture was stirred at -70° C. for 30 minutesto obtain a solution of diphenylisopropylidene sulfurane. The saidsolution at -70° C. was added slowly with stirring under an inertatmosphere to a mixture of 350 mg of 5(RS)methoxy-2,5-dihydrofuran-2-one [prepared by method of Schroeter et al,Liebigs Ann. Chem., Vol. 697 (1966), p. 42] and 15 ml of tetrahydrofurancooled to -90° C. and the mixture was allowed to stand at -78° C. forone hour and then at -50° C. for another hour. The mixture was pouredinto an aqueous monosodium phosphate solution and the mixture wasextracted with methylene chloride. The organic phase was evaporated todryness under reduced pressure and the residue was chromatographed oversilica gel. Elution with a 1-1 ether-petrolum ether mixture yielded 480mg of diphenyl sulfide, 260 mg of (1RS, 5SR)6,6-dimethyl-4(RS)-methoxy-3-oxabicyclo [3,1,0]-hexan-2-one and 100 mgof unreacted lactone.

EXAMPLE 2 (1R, 5S)6,6-dimethyl-4(R)-[1S-(3-phenoxyphenyl)-α-methylmethoxy]-3-oxabicyclo[3,1,0] hexan-2-one STEP A:5R-[1S-(3-phenoxyphenyl)-α-methylmethoxy]-2,5-dihydrofuran-2-one

A mixture of 6.5 g of (S)α-methyl-(3-phenoxyphenyl)methanol, 3.5 g of5-(RS)-hydroxy-2(5H)-furane, 180 mg of p-toluene sulfonic acid and 100ml of anhydrous benzene was refluxed with stirring for 3 hours and wasthen cooled and neutralized with triethylamine. The mixture wasevaporated to dryness under reduced pressure and the 10 g of oilyresidue were chromatographed over silica gel. Elution with a 95-5benzene-ethyl acetate mixture yielded 5.3 g of5-R-[1S-(3-phenoxyphenyl)-α-methylmethoxy]-2,5-dihydrofuran-2-one andthen 2 g of5S-[1S-(3-phenoxyphenyl)-α-methylmethoxy]-2,5-dihydrofuran-2-one.

NMR Spectrum (CDCl₃): 5-R isomer: peaks at 6.07-6.17 ppm (3-hydrogen ofheterocycle); at 6.84-7.5 ppm (4-hydrogen of heterocycle); at 5.72 ppm(5-hydrogen of heterocycle); at 1.47-1.57 ppm (hydrogens of methyl); at4.77-4.87-4.97-5.07 ppm (benzyl hydrogen); at 6.83 to 7.55 ppm(hydrogens of aromatic ring).

NMR Spectrum (CDCl₃): 5-S isomer: peaks at 1.41-1.48 ppm (hydrogens ofmethyl); at 4.66-4.76 ppm and 4.87-4.96 ppm (benzyl hydrogens); at 6.08ppm (2-hydrogen of furanone); at 6.06-6.16 ppm (4-hydrogen of furanone);at 6.75-7.4 ppm (3-hydrogen of furanone); at 6.75 to 7.4 ppm (hydrogensof aromatic ring).

STEP B: (1R, 5S)6,6-dimethyl-4(R)-[1S-(3-phenoxyphenyl)-α-methylmethoxy]-3-oxabicyclo(3,1,0) hexan-2-one

A solution of ≈2.07M of diphenyl isopropylidene sulfurane (prepared from655 mg of the fluoroborate of isopropyl diphenyl sulfonium and 1.5 ml oftert.-butyllithium) was slowly added at -70° C. with stirring under aninert atmosphere to a mixture of 400 mg of the 5R-isomer of Step A in 15ml of tetrahydrofuran and the mixture was stirred at -70° C. for onehour and was then poured into aqueous monosodium phosphate solution. Themixture was extracted with methylene chloride and the organic phase waswashed with water, dried and evaporated to dryness. The residue wascrystallized from a 7-3 petroleum ether-ether mixture to obtain 310 mgof (1R, 5S)6,6-dimethyl-4(R)-[1S-(3-phenoxyphenyl)-α-methylmethoxy]-3-oxabicyclo(3,1,0) hexan-2-one melting at 110° C.

Using the same procedure starting with the 5S isomer of Step A, theproduct was purified by chromatography over silica gel and elution witha 7-3 petroleum ether-ether mixture to obtain (1S, 5R)6,6-dimethyl-4(S)-[1S-(3-phenoxyphenyl)-α-methylmethoxy]-3-oxabicyclo(3,1,0) hexan-2-one.

EXAMPLE 3 (1R, 5S) 6,6-dimethyl-4R-hydroxy-3-oxabicyclo (3,1,0)hexan-2-one

A mixture of 2 g of the (1R, 5S) product of Example 2, 20 ml of acetoneand 5 ml of N aqueous hydrochloric acid was stirred at 20°-25° C. for 2hours and was cooled to 0° to 5° C. The pH was adjusted to about 8 withsodium bicarbonate addition and the mixture was washed with benzene toremove α-methyl-3-phenoxy-benzyl alcohol. The pH was adjusted to 1.5 to2 by addition of concentrated hydrochloric acid and the mixture wasextracted with ethyl acetate. The organic phase was washed with water,dried and evaporated to dryness under reduced pressure to obtain 800 mgof (1R, 5S) 6,6-dimethyl-4R-hydroxy-3-oxabicyclo (3,1,0) hexan-2-onemelting at 120° C. and having specific rotation of [α]_(D) ²⁰ =-110°(c=1% in dimethylformamide).

EXAMPLE 4 (1R, 4R, 5S) 6,6-dimethyl-4-[(1R, 2S, 5R)2-prop-2-yl-5-methylcyclohexyloxy]-3-oxabicyclo (3,1,0) hexan-2-one STEPA: 5R-[(1R, 2S,5R)-2-prop-2-yl-5-methyl-cyclohexyloxy]-2,5-dihydrofuran-2-one

A mixture of 32.5 g of p-menthol, 21 g of5-hydroxy-2,5-dihydrofuran-2-one, 0.2 ml of p-toluene sulfonic acid and300 ml of benzene was refluxed while azeotropically removing the waterof reaction formed and then 4 g of 5-hydroxy-2,5-dihydrofuran-2-one wereadded thereto. The mixture was refluxed for another hour and was thencooled, washed with an aqueous sodium bicarbonate solution and then withwater. The mixture was dried and evaporated to dryness under reducedpressure to obtain 51.6 g of resin. The latter was added to 100 ml ofpetroleum ether (b.p.=35°-70° C.) and the mixture was concentrated. Themixture stood at 0° C. for 17 hours and was vacuum filtered to obtain 15g of crystals melting at 76° C. The mother liquors were evaporated todryness and the residue was taken up in 150 ml of benzene. 200 mg ofp-toluene sulfonic acid were added to the mixture which was thenrefluxed to remove the water of reaction azeotropically. The mixture wascooled and was washed with sodium bicarbonate solution and then withwater, was dried and evaporated to dryness. The residue was crystallizedfrom petroleum ether (b.p.=35°-70° C.) to obtain 10.35 g of productmelting at 76° C. The mother liquors were subjected to an analogoustreatment twice more for additional yields of 5.7 g and 3.4 g,respectively, of product melting at 76° C. for a total of 34.45 g of5R-[(1R, 2S,5R)-2-prop-2-yl-5-methyl-cyclohexyloxy]-2,5-dihydrofuran-2-one meltingat 76° C. and having a specific rotation of [α]_(D) ²⁰ =-139° (c=1.5% inchloroform).

NMR Spectrum (deuterochloroform): peaks at 0.75-0.86 ppm, 0.86-1.0 ppmand 0.83-0.94 ppm (hydrogens of methyls of menthyl); at 3.66 ppm(1-hydrogen of menthyl); at 6.10-6.11-6.13 ppm (5-hydrogen of furanone);at 6.16-6.18 and 6.25-6.26 ppm (3-hydrogen of furanone); at 7.13-7.15ppm and 7.21-7.23 ppm (4-hydrogen of furanone).

STEP B: (1R, 4R, 5S) 6,6-dimethyl-4-[(1R, 2S, 5R)2-prop-2-yl-5-methyl-cyclohexyloxy]-3-oxabicyclo (3,1,0) hexan-2-one

1.2 ml of a solution of 1.5M of tert.-butyllithium in pentane was addedall at once at -80° C. to a suspension of 500 mg of the fluoroborate ofdiphenylisopropyl phosphonium in 10 ml of tetrahydrofuran and themixture was stirred at -80° C. for 30 minutes to obtain a solution ofdiphenyl isopropylidene sulfurane. The said solution was slowly added at-80° C. to a solution of 255 mg of the product of Step A in 10 ml oftetrahydrofuran and the mixture was stirred at -80° C. for one hour andwas poured into a monosodium phosphate solution. The mixture wasextracted with methylene chloride and the organic phase was washed withwater, dried and evaporated to dryness. The residue was chromatographedover silica gel and was eluted with an 8-2 petroleum ether (b.p.=35°-70°C.)-ether mixture to obtain 220 mg of (1R, 4R, 5S) 6,6-dimethyl-4-[ (1R,2S, 5R) 2-prop-2-yl-5-methyl-cyclohexyloxy]-3-oxabicyclo (3,1,0)hexan-2-one melting at 82° C. and having a specific rotation of [α]_(D)²⁰ =-195° (c=4% in chloroform).

NMR Spectrum ((CDCl₃): Peaks at 0.73-1.0 ppm (hydrogens of 6-CH₃ ofmenthyl and hydrogens of methyls of 2-isopropyl of menthyl); at 1.15-1.2ppm (hydrogens of 6-methyls of cyclopropyl ring); at 2.0 ppm (1- and5-hydrogens of cyclopropyl ring); at 3.53 ppm (1-hydrogen of menthyl);at 5.32 ppm (4-hydrogens of lactone ring).

EXAMPLE 5 (1R, 4R, 5S) 6,6-dimethyl-4-hydroxy-3-oxabicyclo (3,1,0)hexan-2-one

8 ml of 0.5N hydrochloric acid solution were slowly added to a solutionof 805 mg of the product of Example 4 in 8 ml of acetone and the mixturewas stirred for 4 hours at 20° C. and was washed a plurality of timeswith petroleum ether (b.p.=35°-70° C.) to remove menthol. The aqueousphase was evaporated to dryness to obtain 360 mg of (1R, 4R, 5S)6,6-dimethyl-4-hydroxy-3-oxabicyclo (3,1,0) hexan-2-one melting at116°-120° C. and having a specific rotation of [α]_(D) ²⁰ =-114° (c=1%in dimethylformamide). Evaporation of the petroleum ether wash liquorsresulted in a practically quantitative yield.

Various modifications of the products and process of the invention maybe made without departing from the spirit or scope thereof and it shouldbe understood that the invention is intended to be limited only asdefined in the appended claims.

What is claimed is:
 1. In the form of pure isomers or in the form ofracemic mixtures in the 5-position, the compounds of the formula##STR7## wherein Z is chiral and is selected from the group consistingof cyclohexyl substituted with alkyl of 1 to 4 carbon atoms and benzylsubstituted on the α-methyl with methyl and on the phenyl with phenoxy.